title: Hyaluronan up-regulates growth and invasion of trophoblasts in an autocrine manner via PI3K/AKT and MAPK/ERK1/2 pathways in early human pregnancy.
abstract: BACKGROUND
  As one of the key molecules in the extracellular matrix in human conceptus, hyaluronan (HA) has been receiving particular attention. Here, we have investigated the expression and regulation of different molecular weight HA on the biological behaviors of primary human trophoblasts during the first trimester of pregnancy.
  
  
  METHODS
  The expression of HA and HA synthetase (HAS) by human first trimester trophoblasts was analyzed in placentae from normal pregnancy or miscarriage by immunochemistry and real-time RT-PCR, respectively. ELISA was used to measure the secretion of HA by primary trophoblasts. The effects of HA on the proliferation, apoptosis and invasiveness of trophoblasts were examined. We also investigated the signaling pathways involved in HA activation in human trophoblasts.
  
  
  RESULTS
  The higher HAS2 expression and HA secretion were observed in normal villi than that of miscarriage, and the primary trophoblasts secreted HA continuously. High molecular weight HA (HMW-HA) and medium molecular weight HA (MMW-HA) promoted proliferation and invasiveness while inhibited apoptosis of trophoblasts. However, low molecular weight HA (LMW-HA) had no obvious effect on the growth or invasiveness of human trophoblasts. In addition, HMW-HA showed more efficiently than MMW-HA on the growth while MMW-HA displayed a more obvious effect on the invasiveness of trophoblasts than HMW-HA. HMW-HA activated PI3K/AKT and MAPK/ERK1/2 signaling pathways in trophoblasts. Blocking PI3K/AKT or MAPK/ERK1/2 signaling inhibited the HA-upregulated growth and invasiveness of human trophoblasts.
  
  
  CONCLUSIONS
  Our results suggest that higher level and greater molecular mass of HA can promote trophoblast growth and invasion in an autocrine manner, which was beneficial to placentation and maintenance of human early pregnancy.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, IBS, Fudan University Shanghai Medical College, Shanghai 200011, China.
authors.forename: R
authors.initials: R
authors.lastname: Zhu
authors.forename: Y-H
authors.initials: YH
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.forename: S-C
authors.initials: SC
authors.lastname: Wang
authors.forename: Ch
authors.initials: Ch
authors.lastname: Sun
authors.forename: H-L
authors.initials: HL
authors.lastname: Piao
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Wang
authors.forename: M-R
authors.initials: MR
authors.lastname: Du
authors.forename: D-J
authors.initials: DJ
authors.lastname: Li
mesh_terms: D000022:Abortion, Spontaneous / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008970:Molecular Weight; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D058539:Phosphatidylinositol 3-Kinase; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Hyaluronan; Invasion; Proliferation; Signal pathway; Trophoblasts